For 8 core NIH-supported laboratories and 11 investigators described in this proposal, liquid chromatography/triple quadrupole mass spectrometry (LC/MS-MS) plays an important role in the quantification of drugs metabolites, and peptides. Sensitivity and selectivity often presents a problem because the analytes are either intrinsically low in abundance, or sample size is very limited, and the analytes generally are present in highly complex biological matrices. The major use of proposed instrument will be the quantification of conventional small-molecule analytes in both basic and clinical NIH-supported projects. A second use will be the quantification of therapeutic and functional proteins in complex biological matrices such as tissues, using methods we are developing. Two instruments were considered for this purpose: the Thermo Finnigan Quantum Ultra AM MS/MS, with the accurate mass measurement option, and the Applied Biosystems API5000 MS/MS. Both instruments represent a significant advance in the state-of-the-art, but present distinct advantages and compromises. Our evaluation of these instruments and the decision as to which instrument best serves the needs of our users is described. The proposed instrument will be integrated into the existing Pharmaceutical Sciences mass spectrometry facility, which is the most comprehensive and heavily utilized academic research facility in the extended geographic region of Western New York. It currently houses three triple quadrupole (LC-MS/MS) instruments, an ion trap (LC/MSn) system, and a newly-acquired linear trap/quadrupole system with multidimensional LC capabilities (MDLC/LTQ). This facility provides instrument access to a diverse population of researchers engaged in basic, applied, and clinical biomedical research. The facility is highly utilized, and has provided investigators with an average of at least 1600 hours of useful data acquisition per instrument over the last 3 calendar years. However, the facility lacks an instrument possessing the sensitivity and selectivity that the proposed instrument would bring, and limitations in the sensitivity and selectivity of the existing MS equipment hinders the described projects in key ways, most often when sample volumes are limited, e.g. in pediatric clinical trials or in small rodent disease models. Furthermore, quantification of marker peptides for target proteins of interest is a growing activity in our facility, and often the proteins of greatest interest are those of low abundance. No other regional facility exists to provide the extended access necessary to support the development of new methods for quantification of low-copy cellular protein transcripts or therapeutically important protein drugs. Given the involvement of our investigators in studies of both basic and clinical sciences, the proposed instrument would have direct, major impact on the development of new therapies for life-threatening diseases, as well as on our basic understanding of biochemical and physiological processes. Relevance The ability to quantify drugs, their metabolites, and/or protein biomarkers in cells and tissues, with high sensitivity and selectivity, is an essential and common need of many research projects that aim to improve the therapy or diagnosis of diseases, or to understand the basic mechanisms biological processes. The proposed instrument will bring to this geographic area the state-of-the art instrumentation necessary, thereby advancing many projects that seek to improve the therapy of serious diseases such as AIDS and cancer. [unreadable] [unreadable] [unreadable]